In this PPG, a multidisciplinary group has been established to analyze the function of a new family of genes that we discovered called TIM (T cell, Immunoglobulin, and Mucin domain containing molecule), specifically focusing on the role of one of its members, TIM-3, in regulating immunity and tolerance in both human diseases and their animal models. We focus on TIM-3 because a series of studies from our PPG group and others demonstrate that TIM-3 plays a critical role in inducing T cell dysfunction/ exhaustion in both chronic viral infections (HIV, HCV, HBV) and cancer (both murine and human) and that there is a defect in TIM-3- mediated regulation in human autoimmune diseases. Accordingly, repressing TIM-3 signals can improve immunity in the setting of chronic viral infection and cancer, while boosting TIM-3 signals can dampen auto- aggressive immune responses in the setting of autoimmunity. However, in order to successfully target Tim-3 therapeutically for the treatment of these diseases, a greater understanding of the molecular mechanisms that govern TIM-3 expression and TIM-3-mediated regulation of T cell responses is required. This PPG brings together three research projects and cores, involving nine talented investigators, to address the regulation of TIM-3 in 3 diseases: multiple sclerosis, cancer, and TB. The proposed studies will utilize and examine animal models and human disease conditions. The three projects are highly integrated and address a common theme: What is the mechanism by which TIM-3 expression and function is dysregulated in various disease states and how can its function be modulated? The main themes of the three projects are: 1. Role of TIM-3 in T cell dysfunction in cancer (Project I: Vijay K. Kuchroo, Ana C. Anderson, and Richard Blumberg, PIs); 2. TIM-3 regulation of CNS autoimmune responses (Project II: David A. Hafler and Joan Goverman, PIs); 3. Role of the IL-27/TIM-3 axis in regulating immunity to TB (Project III: Samuel Behar, and Chen Zhu, PIs). The three cores (Administrative, Transcription, Transgenic/Knock-out Mouse) will support these three projects by providing administrative coordination, a common set of standardized tools, and centralized computational data analysis and sharing across projects, thereby accelerating discovery in an efficient and cost effective manner. As the function of Tim-3 varies across the different inflammatory diseases investigated in the individual projects, the projects in the PPG will instruct each other and together will build a comprehensive understanding of the mechanisms that drive TIM-3-mediated regulation of immunity and tolerance, thus providing critical information for how to exploit this pathway for therapeutic purposes in human disease.